This invention relates generally to growth factors and more specifically, to the influence of transforming growth factor-.beta. (TGF-.beta.) on scar formation and extracellular matrix production in the central nervous system (CNS).
Complete lesions of neural pathways in the adult mammalian CNS are rarely followed by significant functional recovery. After a penetrating injury of the brain or spinal cord, a complex sequence of tissue-specific cellular events is initiated, including a general inflammatory response, angiogenesis, widespread reactive gliosis and the formation of a dense permanent scar of mesodermal origin. These responses are accompanied by transient neuronal sprouting and synaptogenesis, but in most cases the growth responses of neurons are aborted as the glial/meningeal scar becomes organized as discussed in Maxwell et al., Phil. Trans. R. Soc. Lond. 328:479-499 (1990).
There are many theories to explain the failure of axonal growth after injury to the CNS. They attribute the failure to an absence of trophic cues such as growth factors (Logan, Brit. J. Hosp. Med. 43:428-437 (1990)) or to the release of growth inhibitory substances (Schnell & Schwab, Nature 343:269-272 (1990)). The mature scar, with its dense fibrous connective tissue bordered by an astrocytic glia limitans, is a physical barrier to axonal growth. It may be that deficiencies in the extracellular environment of the growing neurites restrict their growth so that they reach the scar tissue after the barrier is formed. Axonal penetration through scar tissue does not occur in the CNS.
Various pathologies are characterized by a deleterious accumulation of extracellular matrix materials. For example, in progressive glomerular disease, extracellular matrix accumulates in the mesangium or along the glomerular basement membrane, eventually causing end-stage disease and uremia. Similarly, adult or acute respiratory distress syndrome (ARDS) involves the accumulation of matrix materials in the lung, while cirrhosis of the liver is characterized by deleterious matrix accumulation evidenced by scarring in the liver.
At present, there are no therapies available to promote successful regeneration and functional reconnection of damaged neural pathways. Any clinical paradigm designed to promote regeneration of central neural pathways must include a regime for reduction of extracellular matrix deposition at the wound site.
Thus, a need exists to determine the factors that regulate accumulation of matrix components in the CNS after injury. A need also exists to control such factors to prevent, limit or treat pathogenic conditions characterized by inappropriate extracellular matrix formation in the CNS. The present invention satisfies these needs and provides related advantages as well.